5-(haloalkyl) picolinic acid and derivatives

ABSTRACT

A 5-(haloalkyl)picolinic acid represented by the general formula,   WHEREIN R1 represents an alkylene group having 3 to 6 carbon atoms and X represents a halogen atom, provided that the halogen atom is attached to the terminal carbon atom of the carbon chain or to the carbon atom at position 3&#39;&#39; in the case of a four-carbon chain, is a novel compound useful as a hypotensive agent. The said novel compound is obtained by reacting a 2-methyl-5(haloalkyl)-pyridine represented by the general formula,   WHEREIN R1 and X have the same meaning as defined above, A. WITH A PEROXIDE TO FORM A 2-METHYL-5-(HALOALKYL)PYRIDINE-Noxide, converting the resulting N-oxide to a 2-hydroxymethyl-5(haloalkyl)pyridine ester by reaction with a carboxylic acid anhydride, hydrolyzing the resulting ester to a 2hydroxymethyl-5-(haloalkyl)-pyridine, and oxidizing the resulting compound with an oxidizing agent; or B. WITH BENZALDEHYDE IN THE PRESENCE OF A DEHYDRATING AGENT TO FORM A 2-STYRYL-5-(HALOALKYL)-PYRIDINE, AND OXIDIZING THE RESULTING STYRYL DERIVATIVE WITH AN OXIDIZING AGENT; OR C. WITH SELENIUM DIOXIDE TO EFFECT OXIDATION.

United States Patent [1 1 Umezawa et al.

[45] Jan. 21, 1975 1 1 S-(HALOALKYL) PICOLINIC ACID AND DERIVATIVES [75]Inventors: Hamao Umezawa; Tomio Takeuchi,

both of Tokyo; Koichi Miyano, Omiya; Hiroaki Hamano, Higashi-Murayama;Wataru Tanaka, Hoya, all of Japan [73] Assignee: Zaiden Hojin BiseibutsuKagaku Kenkyu Kai, Tokyo, Japan [22] Filed: Feb. 6, 1973 21 Appl. No.:330,027

[30] Foreign Application Priority Data Feb. 7, 1972 Japan 47-12840 May30, 1972 Japan 47-52956 June I, 1972 Japan 47-53785 [52] US. Cl.....260/295 R, 260/240 D, 260/290 H1, 260/297 R, 424/266 [51] Int. Cl C07d31/36 [58] Field of Search 260/295 R [56] References Cited UNITED STATESPATENTS 2,766,251 10/1956 Brown 260/295 R 2,868,797 H1959 Cislak 260/295R OTHER PUBLICATIONS Klingsberg, Pyridine And Its Derivatives, Part Two,Pages 97403, 124-27 Interscience Publishers (1961) OD 401 k5 C.2

Steiner et al. Chem. Abstracts, Vol. 59, N0. 1, Pages 562-f to 563-b,July 8, 1963 Klingsberg, Pyridine And Its Derivatives, Part Three, Pages18283, lnterscience Publishers, 1962 OD 40] K5 C.2

Primary ExaminerAlan L. Rotman Attorney, Agent, or Firm-Schuyler, Birch,Swindler, McKie & Beckett 57 ABSTRACT A 5-(haloalkyl)picolinic acidrepresented by the general formula,

Rr-X HOOC (I) wherein R, represents an alkylene group having 3 to 6carbon atoms and X represents a halogen atom, provided that the halogenatom is attached to the terminal carbon atom of the carbon chain or tothe carbon atom at position 3 in the case of a four-carbon chain, is anovel compound useful as a hypotensive agent. The said novel compound isobtained by reacting a 2- methyl-S-(halbalkyl)-pyridine represented bythe general formula,

3 RFX (II) 3 Claims, No Drawings S-(HALOALKYL) PICOLINIC ACID ANDDERIVATIVES This invention relates to a novel 5-(haloalkyl)- picolinicacid represented by the general formula (I) shown below and a processfor producing same.

R- HOOCQTJ'X (I) wherein R represents an alkylene group having 3 to 6carbon atoms and X represents a halogen atom, pro

HBC'ENU/ HECQ R -X (wherein R and X have the same meanings as definedabove),

a. with a peroxide to form a 2-methyl-5-(haloalkyl)- ing agent; or

EEC-K RlnX c. with selenium dioxide to effect oxidation. The process ofthis invention may be represented by the following reaction formulas.

(II) 0 (III) la a HOHQC N (Wherein R and X have the same meanings asdefined above, and R represents a lower alkyl group, a lower haloalkylgroup, or a phenyl group).

The lower alkyl groups represented by R in the above formula includemethyl group, ethyl group, n-propyl group, isopropyl group, butyl group,isobutyl group; and the lower haloalkyl groups represented by R ineludechloromethyl group, bromomethyl group, chloroethyl group, bromoethylgroup, etc.

The process of this invention is explained below in further detail.

ln method (a), at first a Z-methyl-S- (haloalkyl)pyridine (ll) isdissolved in, for example, glacial acetic acid, then admixed withhydrogen peroxide, peracctic acid, perbenzoic acid or perphthalie acid,and allowed to react at a temperature of, for example, 50" to C. forabout 2 to 10 hours to obtain an oily2-methyl-5-(haloalkyl)pyridine-N-oxide (III) in good yields. To theresulting N-oxide (III), is added an acid anhydride, such as aceticanhydride, propionic anhydride, butyric anhydride, benzoic anhydride, rmonochloroacctic anhydride, in slight excess of the theoretical amount.The mixture is allowed to react under reflux for about 30 minutes, thenfreed from the acid anydride and the by-produccd acid, and the residueis distilled under reduced pressure to obtain 2-hydroxy-5-(haloalkyl)pyridine ester (IV). The ester (IV) can be easilyhydrolyzed according to a usual ester decomposing procedure, that is, byheating with an acid or by reacting with an alkali at room temperatureor with heating, to yield a 2-hydroxymethyl5- (haloalkyl)prizine (V).

The 2-hydroxymethyl-5-(haloalkyl)pyridine (V) thus obtained is dissolvedin an organic solvent such as tertbutanol, acetone, or dioxane. To thesolution, is added dropwise, for example, an aqueous solution ofpotassium permanganate, dichromic acid, or potassium dichromatc withcooling, e.g., at around 0 to C., and allowed to react at a temperaturewithin said temperature range or at room temperature for minutes to 2hours. The main reaction product is extracted with an organic solventsuch as chloroform, 1,2- dichloroethane, ether, or benzene, and theextract is dried and freed from the solvent by distillation. The residueis recrystallized from a suitable solvent such as, for example, hexaneor 1,2-dichloroethane to obtain the intended 5-(haloalkyl)picolinic acid(I). When an oxidizing agent such as lead tetraacetate, manganesedioxide, or a complex of chromic anhydride and pyridine was used, thereis formed as an intermediate a 2- formyl-5-(haloalky.l)pyridine whichcan be further oxidized with silver oxide or the like to yield theintended 5-(haloalkyl)picolinic acid (I).

In method (b), a 2-methyl-5-(haloalkyl)-pyridine (II) is reacted withbenzaldehyde in the presence of a carboxylic acid anhydride such asacetic anhydride and propionic anhydride or a combination of acarboxylic acid anhydride with an alkali metal carboxylate such aspotassium acetate and sodium acetate, or in the presence of adehydrating agent such as polyphosphoric acid and the like, at 100 to260 i. for about 26 to 50 hours. After completion of the reaction, thereaction mixture is freed from the unreacted benzaldehyde by steamdistillation, and the residue is extracted with ether. The extractsolution is concentrated and further distilled under reduced pressure toobtain a purified 2- styryl-5-(haloalkyl)pyridine (VI) which can beoxidized in the same manner as in method (a) to yield theintended,5-(haloalkyl)picolinic acid (I).

ln method (c), selenium dioxide is added portionwisc to a2-methyl-5-(haloalkyl)pyridine (II) in a solvent such as dioxane andxylene, or without using a solvent. After completion of the addition,the mixture is heated at 100 to 200C. for about 3 to 10 hours tocomplete the reaction. In order to remove insoluble matters, thereaction mixture is filtered as such when a solvent was used for thereaction, or after dilution with a solvent such as dioxane or ethylacetate when no solvent was used. The filtrate is concentrated underreduced pressure to precipitate the intended 5-(haloalkyl)picolinic acid(I) in the form of crystals which are collected by filtration andrecrystallized from a suitable solvent such as n-hexane or the like toyield a purified product.

The 5-(haloalkyl)picolinic acid of this invention is a novel compoundhaving a distinguished potency as a hypotensive agent.

The efficacy of the compound of this invention is mentioned below withreference to Experimental EXAMPLE EXPERIMENTAL EXAMPLE 1 l-Iypotensiveaction on spontaneously hypertensive rat 5-(Haloalkyl)picolinic acidsobtained by the process of this invention and fusaric acid as a controlwere orally administered to spontaneously hypertensive rats (distributedby Council for the Spontaneously Hypertensive Rat) which had been fittedwith a chronic cannula, and the blood pressure was measured at definiteintervals. The average of minimum blood pressures measured on severalrats divided by the initial blood pressure and expressed in percentagewas referred to as degree of hypotensive effect. Further, the timerequired from the beginning of administration of a pharmaceuticalpreparation until the blood pressure restored its initial value(persistence time) was measured. The results obtained were as shown inTable l. LD of the compounds of this invention for a normal mouse wasalso shown in Table l. The measurements were carried out according tothe method of I. Nagatsu, T. Nagatsu, K. Mizutani, H. Umezawa, M.Matsuzaki and T. Taniguchi [Nature, 230, 381 (1971)].

TABLE 1 Hypotensive effect of 5-(haloalkyl)picolinic acids onhypertensive rats, persistence time of the effect (administrative dose,25 mg/kg), and LD for a normal mouse Substituent group Degree of Exp. atposition 5 of hypotenig ig Numger LD5O No. 5(haloalkyl) sive c 0 g/ g)picolinic acid efazet our ases 1 -(CH Cl 75.0 48 6 50050 2 (CH Cl 72.072 5 4701 5 -(CH Cl s2. 5 72 5 5501 4 -(CH Cl 95.0 72 4 6501550 5-(CH2)5BI- 70.0 72 4 500150 6 -(CH2) 4B1 85 .0 72 4 60050 7 -(CH2)4F68.0 72 6 350150 Substituent group Degree of Exp. at position 5 ofhypoteni ig 3? LD5 No. 5-(haloalkyllsive (hour) cases (mg/kg) picolinicacid efisfifi 9 CH2 QCHCHB Fusaric acid 10 -(CH CH 82.5 72 4 56030(Control) Note: *1 Degree of hypotensive effect Average minimum bloodpressure/Initial blood pressure X 100 *2 Time required from thebeginning of adminstration of a pharmaceutical preparation until theblood pressure restores its initial value.

The results obtained in the above-mentioned Experimental Example 1 areillustrative of the distinguished hypotensive effect of the present5-(haloalkyl)picolinic acids.

The Z-methyl-S-(haloalkyl)pyridine for use as a starting material in theprocess of this invention can be prepared by reacting2-methyI-S-ethynylpyridine with a Grignard compound, a lower alkyl metalcompound, sodium hydride, or an alkali metal amide, then reacting thereaction product with ethylene oxide, an aliphatic aldehyde, or analiphatic ketone, reducing the reaction product to aZ-methyl-S-(hydroxyalkyl)pyridine, and reacting the resultinghydroxyalkyl compound with ptoluenesulfonyl chloride in anhydrouspyridine for a long period of time, or reacting the intermediatetosylate with a halide such as lithium chloride or lithium bromide, ordirectly halogenating said hydroxyalkyl compound with a halogenatingagent such as thionyl chloride in pyridine.

Alternatively, a 2-methyl-5-(chloroalkyl)-pyridine may be obtained byreacting 2-methyl-5- ethynylpyridine with a compound represented by thegeneral formula,

(wherein R represents an amide group, a lower alkyl group, or a phenylgroup, and M represents an alkali metal atom) or with a Grignardcompound, further reacting the resulting product with a compoundrepresented by the general formula,

wherein X represents Br or OTs (Ts stands for a tosyl group), and Rrepresents an alkylene group having 3 to 6 carbon atoms, andcatalytically reducing the reaction product in a usual way, e.g., in thepresence of a catalyst such as palladium or Raney nickel. The said 2-methyl-S-(chloroalkyl)pyridine may be converted to a corresponding2-methyl-5-(bromoalkyl)pyridine or 2- methyl 5-(fluoroalkyl)pyridine byreaction with hydrobromic acid or by heating with potassium fluoride indiethylene glycol.

The invention is illustrated below in detail with reference to Examples.

EXAMPLE 1 Synthesis of 5-(3-chloro-n-propyl)picolinic acid 2.73 Grams of2-methyl-5-(3'-chloro-n-propyl)- pyridine in 10 ml of acetic acid isheated with 1.6 ml of 30 percent-hydrogen peroxide at to C. for 3 hours.Additional 1.2 ml of 30 percent-hydrogen peroxide is added to thereaction mixture and heated at 70 to 80C. for further 9 hours. Aftercompletion of the reaction, the reaction mixture is concentrated underreduced pressure to /3 the original volume. diluted with water torestore the original volume. again concentrated to /3 the originalvolume, and extracted 5 times with each 10 ml of ether. The ether layerwas added with anhydrous potassium carbonate to remove the acetic acid,and then freed from the ether by distillation to obtain quantitatively2-methyl-5-(3-chloro-n-propyl)pyridineN-oxide in the form of a paleyellow oil (a strong absorption due to N-oxide appears at v 1270 cm inIR spectrum). The N-oxide is dissolved in 1 ml of acetic anhydride andadded dropwise to 4 g of acetic anhydride which has been refluxed withheating and stirring. After completion of the addition, the mixture iskept under reflux with stirring for further 20 minutes and freed fromthe acetic anhydride under reduced pressure. Crude2-acetoxymethyl-5-(3-chloro-npropyl)pyridine is obtained as a brownishblack oil (strong absorption bands due to an ester appear at v 1735 cmand v 1220 cm in IR spectrum).

To the oily residue, is added 20 ml of concentrated hydrochloric acid,and refluxed for 3 hours. The reaction mixture is concentrated underreduced pressure to k the volume, made alkaline with aqueous ammoniaunder ice-cooling, and extracted three times with 50 ml of ether. Theethereal layer is dried over anhydrous potassium carbonate and freedfrom the ether by distillation to obtain 2.26 g of an oily residue, paleblack. To this unpurified 5-(3-chloro-n-propyl)-2-hydroxymethylpyridine,is added 5 ml of water, followed by gradual, dropwise addition of asolution of 2.8 g of potassium permanganate in ml of water, while beingstirred vigorously and cooled in ice. After completion of the dropwiseaddition, stirring is continued for one hour at 0C. To the mixture, isadded 1 ml of methanol to decompose the excess potassium permanganateand stirred at 50C. for 20 minutes.

The precipitated manganese dioxide is collected by filtration and washedthoroughly with ml of boiling water. The filtrate and washings arecombined, adjusted to pH 5 with dilute hydrochloric acid, concentratedunder reduced pressure to 20 ml, and extracted four times with 40 ml ofether. The ethereal layer is Calculated (C H NO CI) Found C 54. l 54.00H 5.05 5.0l N 7.02 7.27

In a similar manner as above, compounds shown in After completion of thereaction, the acetic anhydride is removed from the reaction mixture bydistillation under reduced pressure to obtain 2-acetoxymethyl-5-(4-chloro-n-butyl)pyridine. This base is dissolved in 50 ml ofconcentrated hydrochloric acid, refluxed for 3 hours, cooled, madeslightly alkaline with aqueous ammonia, and extracted with ether. Theethereal layer is dried over potassium carbonate and freed from theether by distillation. Oily 2-hydroxymethyl-5-(4-chloro-n-butyl)pyridine is obtained.

To ml of benzene containing 236 g of lead tetraacetate, while beingrefluxed with stirring, is added above-obtained 2- After dropwise 1.06 gof the hydroxymethyl-5-(4'-chloro-n-butyl )pyridine.

Table 2 were synthesized. 15 completion of the addition, the mixture isrefluxed with Table 2 St '0 t 1 End d ct Analysis ar lng ma elila pro uYield l i F r ula Found (calculated) ?Methyl-5halo 5-Ha1oalkyl- Eg malkylpyridine picolinic acid C H N {(lllol'5lll -(C'li )3l3r 44.1? 4.116 0.

4 a) 6 122 12,' CH NOB ll'gh N H000 N 2 J 9 1O- 2 r ((1) (1L) 5' (I A)(0n5) 01 j--(cH c1 56.44 53/: 6. L l 50 104 105 0 a NO 01 n 0 N HOOC N10 12 2 (562D (566) (GM?) 46.29 4.67 5.65 LQT I' @T M 29 106 107 C H NOBr H30 N H000 N (46.55) (4.69) (5.4.5)

'(CH F -(CH F 60.67 6.11 7.214 p 4 flg 2 4 45 100 101 c a no r K (011 x01 f ,-'(CH Cl 58.21 6.23 6.19 0 L 47 115 114 c H N0 1 N HOOC N l1 l4 2(58.05) 6.02) (6.15)

4; (0H F (011 F 62 66 6.59 6.58 H L T 2 5 Q 2 5 42 110. 111 C H NO F(011)01 (CH) 01 59.55 5.80 6.02 H 2 6 2 6 4a 103 104 C 2H 6NO2Cl (CHcaca CH CHCH 6.0 .6 6. r n-cQ 2 HOOC Q 2)21 3 114 115 C H NO Cl 5 9 5 557 EXAMPLE 2 stirring for minutes, then allowed to stand, and theSynthesis (1) of 5-(4-chloro-n-butyl)-picolinic acid To 12.5 g of2-methyl-5-(4-chloro-n-butyl)-pyridine dissolved in 60 ml of aceticacid, is added dropwise 18 ml of 30 percent-hydrogen peroxide, and themixture is heated at 70 to 80C. for 10 hours.

After completion of the reaction, the excess hydrogen peroxide isdecomposed with sodium bisulfite, and the reaction mixture is extractedwith ether. The ethereal layer is washed with an aqueous solution ofsodium carbonate, then with water, dried over anhydrous sodium sulfate,and freed from the ether by distillation to obtain oily2-methyl-5-(4'-chloro-n-butyl)pyridine-N- oxide. The resulting N-oxideis added to 60 ml of acetic anhydride and refluxed with heating for onehour.

precipitated lead diacetate is separated by filtration. The filtrate iswashed with water, freed from the acetic acid with potassium carbonate,and then freed from the benzene by distillation under reduced pressureto obtain 0.62 g of 2-formyl-5-(4-chloro-n-butyl)pyridine.

with ether. On removing the ether, colorless cystals are obtained andthen they are recrystallized from ligroinhexane (1 2) to yield5-(4-chloro-n-butyl)picolinic acid. Yield: 0.58 g (52 percent).

and evaporated to dryness. The residue is recrystallized from ligroin toobtain 5-(5-chloro-n-pentyl)picolinic acid having a melting point ofll3-ll4C. Yield: 1.85 g (41 percent).

Note:

* Yield 01' lllc end product. As l'icrotc.

EXAMPLE 3 5 REFERENTIAL EXAMPLE Synthesis of5-(5-chloro-n-pentyl)p1col1n1c acid I 1 4 A mixture f 1 97 g f 2Synthesis of 2-methyl-5-(3 -chloro-n-propyl)pyridmechloropentyl)pyridine, 3.18 g of benzaldehyde, and A of g of y- 3.16 gof acetic anhydride is heated at 160C for 24 I propynpyndmei g of P'f fchlorlde, hours. After being cooled, the reaction mixture is acidi and15 ml of anhydrous y q stlrreq at for fied by addition of dilutehydrochloric acid, and steam id reactlorzjrgllxwfe f g go 50 m] of isintroduced into the acidified mixture to remove the S wate an extracteour tlmes ml of l unreacted benzaldehyde by distillation. The residue ish ethereal layers are Fombmedt washed three nines made alkaline andextracted with ether. The ethereal 15 wlth 30 ml of water dned Overanhydrous Potasslum layfir is washfid with Water dried over potassiumCap Carbonate, and freed from the ether by distillation. The bonate, anddistilled in vacuo to obtain 1.1 g of an oily i lfi d ir lg gk flir'l gmatter boiling at l60-l65C./0.5 mmHg. The molecu- M mmHg. P y W E p larweight was determined from the massspectrum to be 285, and the oilymatter was confirmed to be a 2- styryl derivative. In 20 ml of acetone,is dissolved 1.1g of the styryl derivative and to the resulting solutionis NMR -y 1.67 (IH d 0.4 pm) added 2.15 g of potassium permanganateportionwise Y dd ppm) b a 'yZ.96(lHdl.3ppm) while maintaming at 5 to 10C. After completlon of 6.5l (2H 1 1.1 ppm) the addition. the mixture isstirred at 10 to 15C. for 7 717mm H 17.50 (3H s) 3 hours. Theprec1p1tated manganese dioxide 15 sepa- 7,93 (2H rated by filtration andwashed with acetone. The filmy? k 7 I06 trate and washings are combinedand treated in the (one same manner as in Example 1 to obtain crude5-(5- chlorine atom) chloro-n-pentyl)picolinic acid. Yield: 440 mg (50per cent). On recrystallization from ligroin, a purified product meltingat l l3l l4C. is obtained. El pomt i P g?- t 138C men ary ana ysis opicra 0: EXAMPLE 4 "1; Synthesis of 5 (5 -chloro-n'pentyl)p1col1n1c ac1dCulculmcd (CISHUNJOKII) Found In 50 ml of pyndmc, are suspended 4 g 012-mcthyl-5- (5'-chloro-n-pentyl)pyridine and 3.3 g of selenium di- 2 23oxide, and stirred under reflux for 3 hours. The metallic N 4: 33selenium precipitated is separated by filtration and washed with water.Steam is introduced into the reaction mixture to remove the pyridine bydistillation. The In a similar manner as above, compounds shown inaqueous solution is decolorized with activated carbon Table 3 weresynthesized.

Table 3 Starting material End product Boiling 2 na](.ys]i:s l($t pointYield Formula Foun ca on a e 2-l lothy]" -hyd1-oxy 2-l lethyl-5-halo-0.) (7 (melting point) alkylpyi'idino alkylpyridine (mmHg) C H N .77 (1:11 .);,-c11c11 q-(01-1;,) c11c11- 72 (7 5 11 0 131 45.56 4.16 1?, 1

l 1 68 N 1111 N 01 (2) (131 152 0) (46.58) (4.12) (15.85)

(1:11;1) o11 WH MF '14 0 11 11 0 1 48.49 4.52 14.14 I V I 51 i N Hie N(0.85) (122 123C) (48.22) (4.28) (14 9) 011 1 011 c11 01 e0 87 C 5H N OCl 46 .56 4 15 15 5? H N N (0.15) (114 115 (46.40) (4.18) (15 '14) I/IJ.((JIUMOH (CHIHMBF 0 C H N O B1' 46.3 2 4.00 llnfi 1 1 G? H N (0.10)(1'49 144 (1) (44.5 (4.1 (13.1

REFERENTIAL EXAMPLE 2 Synthesis of 2-methyl-5-(3'-chloro-n-propyl)pyridine To a mixed solution comprising 4.08 g of 2-methyl-5-(3'-hydroxy-n-propyl)pyridine and 2.35 g of anhydrous pyridine, whilebeing cooled in ice, is added dropwise 3.38 g of thionyl chloride at thetemperature not exceeding 40C. The solution becomes dark brown. Aftercompletion of the addition, the solution is stirred at room temperaturefor 3 hours and the reaction mixture is poured into 30 ml of ice water.After addition of 2 ml of concentrated aqueous ammonia, the mixture isextracted three times with ml of ether. The ether layer is washed with20 ml of water, dried over anhydrous potassium carbonate, and freed fromthe ether by distillation. The residue is distilled in vacuo to obtain2.73 g of 2-methyl-5-(3'-chloro-n-propyl)pyridine. Upon identification,the product was found to be the same substance as2-methyl-5-(3'-chloro-npropyl)pyridine obtained in Referential Example1.

REFERENTIAL EXAMPLE 3 Synthesis of 2-methyl-5-(5'-chloro-n-pentyl)-pyridine To 600 ml of liquid ammonia, is added 150 mg of ferric nitrate,followed by, while being stirred, gradual addition of 12.7 g of metallicsodium cut to small pieces. After completion of the addition, graysodium amide deposits in about 30 minutes. To the mixture, is added 58.6g of 2-methyl-S-ethynylpyridine in small portions. After the addition,stirring is continued for 3 hours. To the reaction mixture, is addeddropwise 158 g of l-bromo-3-chloropropane. After completion of theaddition, stirring is continued for 4 hours, and then the liquid ammoniais removed under reduced pressure. To the residue, is added 500 ml ofwater and extracted 4 times with 200 ml of ether. The ethereal layer isextracted with dilute hydrochloric acid. The hydrochloric acid layer iswashed with 200 ml of ether, made alkaline with aqueous ammonia whilebeing cooled in ice, and extracted three times with 200 ml of ether. Theethereal layer is dried over anhydrous potassium carbonate and freedfrom the ether by distillation. The oily residue is dissolved in 300 mlof methyl alcohol and reduced in an autoclave in the presence of Raneynickel under a hydrogen pressure of 50 kg/cm at 30 to 50C. for 2 hours.After separation of the Raney nickel by filtration, the methyl alcoholis removed from the reaction mixture by distillation. The residue isdistilled in vacuo to' obtain 63 g (65 percent yield) of 2-methyl-5-(5'-chloro-n-pentyl)pyridine as a colorless oil boiling at 97-98C/0.15mmHg.

Melting point of picrate: 107-108C Elementary analysis of picrate:

REFERENTIAL EXAMPLE 4 Synthesis of2-methyl-5-(6-chloro-n-hexyl)-pyridine To 10 ml of anhydroustetrahydrofuran, is added 1.15 g of metallic sodium in thread formfollowed by dropwise addition of 5.85 g of 2-methyl-5- ethynylpyridinedissolved in 10 ml of anhydrous tetrahydrofuran. After completion of theaddition, stirring is continued for 5 hours under reflux. Then, to themixture is added 13 g of 4-chlorobutyl p-toluenesulfonate. The mixtureis stirred for 2 hours under reflux, transferred into 50 ml of icewater, and extracted with ether. The ethereal layer is treated in thesame manner as in Referential Example 1 to obtain2-methyl-5-(6-ch1oron-hexyl)-pyridine in a yield of 57 percent. Boilingpoint: 101C/0.09 mmHg.

REFERENTIAL EXAMPLE 5 Synthesis of pyridine A mixture of 6.65 g of2-methyl-5-(5'-chloro-npentyl)pyridine, 20 g of diethylene glycol, and3.0 g ofdiethylene glycol, and 3.0 g of potassium fluoride is allowed toreact with stirring at C. for 25 hours. After being cooled by standing,the reaction mixture is added with 30 ml of water and extracted fourtimes with 20 ml of ether. The ethereal layer is washed witth 50 ml ofwater, dried over anhydrous potassium carbonate, and freed from theether by distillation. The residue is distilled under reduced pressuretoobtain 2.38 g (39 percent yield) off colorless 2-methyl-5-(5-fluoro-n-pentyl)pyridine boiling at 68C/0.2 mmHg.

What is claimed is:

l. A 5-(haloalkyl)pico1inic acid represented by the general formula,

R X HOOC-Q l wherein R represents an alkylene group having 3 to 6 carbonatoms and X represents a halogen atom, provided that the halogen atom isattached to the terminal carbon atom of the carbon chain or to thecarbon atom at position 3' in the case of a four-carbon chain.

2. A compound according to claim 1, wherein the 5-(haloalkyl)picolinieacid is a S-(halo-nbutyl)picolinic acid represented by the generalformula,

wherein X represents a halogen atom.

3. A compound according to claim 1, wherein the 5-(haloalkyl)picolinicacid is 5-(chloro-nbutyl)picolinic acid represented by the formula,

CH -Cl Disclaimer 3,862,159.Hama0 Umezawa and Tomio Takeuchz', Tokyo,Koz'chz' Miyzmo, Omiya, HTOa/Zri Hamano, Higashi-Murayama, and WatamTanalca, Hoya, Japan. 5-(HAL()ALKYL)PICOLINIC ACID AND DE- RIVATIVES.Patent dated Jan. 21, 1975. Disclaimer filed Mar. 19, 1976, by theassignee, Zaz'drm H ojz'n Biseibutsu Kagaku Kenkyu Kai.

Hereby enters this disclaimer to claim 1 of said patent.

[Ofiicial Gazette May 25, 1 976.]

UNITED STATES PATENT OFFICE EERTIFIQATE 0F CORRECTION Patent No. 3862,159 Dated January 21, 1975 Inventor(s) Hamao UmeZaWa et a1 It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

In the title page, the assignee "Zaiden Hojin Biseibutsu Kagaku KenkyuKai" has been corrected to Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Inthe foreign application priority data, the following has been 5,Japanaoaaonumauloooon Signed and sealed this 15th day of July 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C, MASON Commissioner of Patents Attesting Officerand Trademarks

2. A compound according to claim 1, wherein the 5-(haloalkyl)picolinicacid is a 5-(halo-n-butyl)picolinic acid represented by the generalformula,
 3. A compound according to claim 1, wherein the5-(haloalkyl)picolinic acid is 5-(chloro-n-butyl)picolinic acidrepresented by the formula,